The present invention relates to a series of new heterocyclic compounds having tachykinin receptor antagonist activity. It also provides methods and compositions using them for therapeutic and prophylactic purposes, as well as processes for their preparation and intermediates used in their preparation.
The presence in the mammalian body of the various forms of tachykinin is associated with a variety of diseases and disorders, including respiratory diseases, such as asthma, bronchitis, rhinitis and coughs; allergies; ophthalmic inflammatory diseases, such as conjunctivitis and spring catarrh; dermal diseases, such as contact dermatitis, atopic dermatosis and urticaria; inflammatory diseases, such as rheumatism and arthrosis deformans; pain, such as migraine, headache and toothache; central nervous system diseases, such as anxiety and Alzheimer's disease; and gastrointestinal diseases, such as colitis; and cystitis; and many others. Inhibition of the activity of these forms of tachykinin will, therefore, result in a new therapy and/or prophylaxis for these diseases and disorders.
The compounds of the present invention exhibits antagonism generally to tachykinin receptors, but especially to the receptors for substance P (which receptors are generally referred to as "neurokinin 1 receptors"--NK.sub.1) and the receptors for neurokinin A (which receptors are generally referred to as "neurokinin 2 receptors"--NK.sub.2). It is a particular advantage of the compounds of the present invention that they exhibit antagonism to both of these receptors, a so-called "dual effect".
Compounds which are structurally close to those of the present invention are disclosed in FR 2729952, FR 2729953 and FR 2729954. However, these are selective for the NK.sub.1 receptors and none of these compounds exhibits the dual effects of the compounds of the present invention.
A few low molecular weight non-peptide compounds are known to exhibit antagonism to both of these receptors, for example some of the compounds disclosed in WO 9429309 (1994), WO 9417045 (1994), WO 9426735 (1994) and WO 9528389 (1995) exhibit such an effect. Typical examples of compounds which are disclosed in these documents are: ##STR2##
However, oral absorption of these compounds is poor. As a result, these prior art compounds cannot be administered by mouth and must be administered parenterally, for example by injection. It is well known in the medical field that administration of any drug by injection is undesirable, as either the patient must be trained (and some patients are inherently untrainable) or the drug must be administered by experienced staff, which is expensive and inconvenient both for the patient and the staff.
There is, therefore, a need for a new tachykinin receptor antagonist which exhibits the aforementioned dual effects, and which has good oral absorption and a low toxicity.
We have now discovered a series of new compounds which exhibit an activity against the NK.sub.1 receptors which is at least equal to that of the prior art compounds showing a dual effect and which unexpectedly exhibit a much stronger activity against the NK.sub.2 receptors.